Biotransformation

Question 1

Consequences of biotransformation

Answer 1

activation of pro-drug

active compound–>active compound

inactivation

Question 2

Sites of biotransformation

Answer 2

liver mainly

also GI, lungs, skin, kidneys

Question 3

What is the first-pass effect

Answer 3

oral drugs absorbed in SI–>liver–> hepatic portal system-> extensive metabolism

***limits bioavailability of some drugs

Question 4

What drugs have bioavailability increased via GI flora?

Answer 4

estrogens used in contraception d/t recycling of metabolites

Question 5

What is an example of a drug that undergoes extensive first pass biotransformation and only 25% reaches blood?

Answer 5

morphine

Question 6

Is phase 1 of metabolism catabolic or anabolic

Answer 6

catabolic–>inactivates drug via unmasking functional group to make it polar

Question 7

Where are phase 1 enzymes located

Answer 7

lipophilic ER membranes of liver

Question 8

What is the function of phase 2

Answer 8

conjugate–>more excretable

ex: glucuronidation

anabolic

Question 9

What phase do CYPs work in

Answer 9

phase 1

Question 10

What CYP is involved in 50% drug metabolism

Answer 10

CYP 3A4

Question 11

What CYPs are most important

Answer 11

1A2

2A6

2D6

2E1

3A4

Question 12

Where do CYPs get their reducing power

Answer 12

NADPH (use O2 and H to oxidize drugs and make polar)

Question 13

Genetic defect in pseudocholinesterase has what effect

Answer 13

metabolize succinylcholine 50% the rate as normal people

Question 14

Why can AR trait, which has decrease in N-acetyltransferase, cause hepatotoxicity?

Answer 14

caffeine, isoniazid, hydralazine metabolized at slower rates since less enzyme–> builds up in liver and causes hepatitis

Question 15

What enzymes are involved in phase 1

Answer 15

CYPs
FMO
hydrolases

Question 16

What are phase 2 enzymes

Answer 16

transferases

Question 17

Inducer examples

Answer 17

phenobarbital

chronic ethanol

tobacco smoke (aromatic hydrocarbons)

rifampin

St John’s wort

Question 18

What do inducers do to drug levels

Answer 18

activate enzymes, so less drug in body

Question 19

What happens to clearance with inducers?

Answer 19

inducers decrease half-life, so clearances increases

Question 20

Prominent inhibitors

Answer 20

grapefruit juice

allopurinol and mercaptopurine given together–> increases merc. toxicity

Question 21

What is the grapefruit juice effect

Answer 21

grapefruit with drugs can irreversibly inhibit CYP 3A4

Question 22

What makes neonates highly susceptible to drug toxicity

Answer 22

underdeveloped BBB, weak biotransforming activity, immature excretion

Question 23

What is the most important factor for decreased drug metabolism in elderly

Answer 23

liver and kidney disease

not really drug dependent d/t half-life

Question 24

Give example of biotransformation to toxic product

Answer 24

acetaminophen-induced hepatotoxicity

intake exceeds therapeutic dose, GSH in liver is depleted faster than regenerated–> toxic metabolites accumulate

Question 25

Explain polymorphism in CYP 2D6

Answer 25

codeine–> morphine (200 x agonist) normally

if polymorphism, insufficient pain relief and increased risk for side effects (resp depression, drowsiness)

Question 26

Explain polymorphism in CYP 2C 19

Answer 26

decreases active metabolite formation and reduces Clopidogrel’s antiplatelet activity

–> severe risk for cardiovascular events

Question 27

Explain polymorphism in G6PD

Answer 27

hemolysis when using drugs for lowering uric acid

Question 28

Phase 0

Answer 28

microdosing to human volunteers

Question 29

Phase 1

Answer 29

25-50 people

aware what testing is being conducted

absorption, half life, metabolism

Question 30

Phase 2

Answer 30

100-200 people

single blind (physician knows)

placebo, dosing requirements, efficacy, toxicities

Question 31

Phase 3

Answer 31

300-3000 people
safety
crossover and double blind

Question 32

Phase 4

Answer 32

after market approval

monitor in population